[unreadable] [unreadable] Currently, first-line treatment of resectable solid tumors most commonly involves surgery followed by a regimen of chemotherapy and/or radiation. Unfortunately, this strategy often fails because of recurrent or metastatic disease. To change this paradigm, new cancer therapies must deliver multifaceted therapeutics to destroy the heterogeneous population of tumor cells present within solid tumors prior to surgical removal. The current proposal seeks to develop such tumor-targeted nanotherapies on a pegylated colloidal gold nanoparticle platform (cAu) designed to deliver a combination of potent anti-cancer drugs to solid tumors. The first drug developed (designated CYT-0691) actively targets and sequesters human tumor necrosis factor alpha (TNF) in solid tumors while avoiding uptake and clearance by the reticuloendothelial system (RES). The drug is comprised of TNF and thiolated polyethylene glycol (an RES avoidance molecule) that are covalently bound, as individual molecules, to the surface of 26 nm cAu nanoparticles. This proposal seeks to use TNF bound to pegylated cAu nanoparticles as the core of a family of new combinational cancer nanotherapies. These new nanotherapies will be assembled on a single particle of pegylated cAu and are designed to deliver both TNF and a second therapeutic that synergizes with the known actions of TNF on solid tumors. The multivalent nature of the proposed cAu nanodrugs will require us to further our current understanding of the nanoparticle platform and the interaction of the putative therapeutics with the cAu nanoparticle's surface. To meet this challenge, Cytlmmune has assembled a multidisciplinary team of experts to address the basic and applied challenges of making pegylated cAu nanoparticles a platform technology for developing tumor-targeted nanotherapeutics. The expertise of each team member will be brought to bear in addressing specific issues of surface binding chemistries to cAu nanoparticles, the synthesis and characterization of the cAu bound drugs, and the biologic characterization of each new pegylated cAu nanoparticle vector. Cytlmmune's collaborators include Dr. David Kingson of Virginia Tech., Dr. Dan Goia from Clarkson University, Drs. Viktor Struzhkin and Andrew Steele of the Geophysical Laboratory of the Carnegie Institute, and Drs. Paras Prasad and Haridas Pudavar of the Department of Chemistry at the University of Buffalo. [unreadable] [unreadable] [unreadable]